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Fig A2. Relationship of distribution of baseline androgen levels and estimate of median survival in all patients. (A) Testosterone; (B) androstenedione; (C) dehydroepiandrosterone sulfate (DHEAS).
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Purpose:
In the phase III study COU-AA-301, abiraterone acetate (AA) plus prednisone (P) prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel administration. In this article, we investigate the relationship between baseline serum androgen (SA) levels and OS.
Patients and methods:...
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Recently new drugs targeting androgen-dependent axis have been approved for the treatment of castration-resistant prostate cancer (CRPC) - Zytiga and Xtandi (formerly MDV3100), several other candidates (for example, ARN-509) are in early phases of clinical trials. However despite significant improvement in overall survival with new treatments it is...
Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen...
Citations
... Rat models of prostate cancer suggest a protective role for DHEA against the development of the disease [54]. But in patients, lower serum levels of DHEA align with more aggressive prostate cancer characteristics, such as a high Gleason score, advanced clinical stage, and notably, a worse prognosis in hormone-naïve prostate cancer and poorer cancer-specific survival in metastatic castrationresistant prostate cancer (mCRPC) patients [55]. These findings suggest that DHEA is a potent uncompetitive inhibitor of G6PD, and a lower level of DHEA in patients might cause upregulation of G6PD and promote tumor growth and metastasis. ...
Prostate cancer (PC) stands as the most frequently diagnosed non-skin cancer and ranks as the second highest cause of cancer-related deaths among men in the United States. For those facing non-metastatic PC necessitating intervention, solely local treatments may not suffice, leading to a possible transition toward systemic therapies, including androgen deprivation therapy (ADT), chemotherapy, and therapies targeting androgen. Yet, these systemic treatments often bring about considerable adverse effects. Additionally, it is observed that overweight men are at a higher risk of developing aggressive forms of PC, advancing to metastatic stages, and succumbing to the disease. Consequently, there is a pressing demand for new treatment options that carry fewer side effects and enhance the current standard treatments, particularly for the majority of American men who are overweight or obese. In this article, we will review the metabolic response to ADT and how lifestyle modulation can mitigate these ADT-associated metabolic responses with a particular focus on the two clinical trials, Carbohydrate and Prostate Study 1 (CAPS1) and Carbohydrate and Prostate Study 2 (CAPS2), which tested the effects of low-carbohydrate diets on the metabolic side effects of ADT and PC progression, respectively. Furthermore, we will summarize the findings of serum metabolomic studies to elucidate the potential mechanisms by which ADT and low-carbohydrate diets can affect the metabolic response to mitigate the metabolic side effects while maximizing therapeutic efficacy.
... These treatments aim to reduce the tumour burden and improve patient survival [6]. Furthermore, ADT with LHRH analogues reduces testicular androgen production without affecting adrenal or intracrine androgen synthesis [7]. Androgens such as androstenedione are AR agonists, which may influence cancer progression. ...
Background: Androgen deprivation therapy (ADT) is a mainstay of prostate cancer in both adjuvant and palliative settings. Since androgens are crucial for functional status and psychological functions, we evaluated whether blood testosterone, androstenedione, or DHEA concentrations were associated with functional status and psychological alterations in patients with localised (PCa) or metastatic prostate cancer (mPCa) receiving ADT with analogues of luteinising hormone-releasing hormone (LHRH). Methods: The five Fried criteria were considered to identify frailty syndrome. In addition, complementary evaluations were carried out to measure other variables of interest. Sleep quality was assessed using the Athens Insomnia Scale, cognitive functions were assessed using the Mini-Mental State Examination, and symptoms of depression were measured using the Yesavage Geriatric Depression Scale. Logistic regression analysis was performed to determine if the androgens level could be related to frailty syndrome, sleep impairment, depressive symptoms, and cognitive functions. Results: The results of the multivariate analyses show that high concentrations of androstenedione were significantly associated with frailty syndrome in both groups (p = 0.018; odds ratio = 4.66, 95% confidence interval [1.30–16.6]). There were significant relationships between frailty syndrome and the systemic concentration of androstenedione (p = 0.01), but not the concentration of testosterone (p = 0.60) or DHEA (p = 0.42). In addition, the results of the non-parametric tests show significant results between a decreased gait speed in the two groups (metastatic and localised) and the concentration of androstenedione (p = 0.015). High androstenedione levels were associated with a slow walking speed in the mCaP group (p = 0.016), while high testosterone levels were associated with a better walking speed in the localised CaP group (p = 0.03). For the concentration of androstenedione in plasma, the area under the curve was 0.72, with a 95% CI of 0.55–0.88 with acceptable values, and with a cut-off point of 4.51 pg/mL, a sensitivity of 82.9%, and specificity of 53.8%. No relationships between the concentration of androgens in plasma and sleep quality, cognitive functions, or symptoms of depression suggest that the changes were specific to frailty syndrome. Conclusions: Further research into the role of androstenedione should be evaluated in follow-up studies in order to recommend its use as a suitable biomarker of frailty syndrome in prostate cancer patients.
... Circulating androgens have a clear relationship with PCa progression, as illustrated by the therapeutic effect of androgen suppression in metastatic disease, maintained even in later stages of disease. 30,31 Serum androgens are required for the normal prostate growth and for the development of PCa, but how they act in the initial carcinogenesis is unknown, with distinct models being proposed. [32][33][34][35] The wide range of results in the literature is probably due to the complexity of androgen physiology and assessment. ...
Objectives:
The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study.
Methods:
Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status.
Results:
A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers.
Conclusions:
Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.
... 6,16,[19][20][21] In the metastatic clinical condition, data from clinical phase 3 studies performed in castration-sensitive and castration-resistant PCa patients clearly indicated that despite reducing T to castrate levels, additional AR blockade with AR-targeting agents further improved survival outcomes. [22][23][24][25][26] These findings supported that additional steroid hormones are involved in progression. In localized disease settings, in men under ADT therapy recruited as part of the PR-7 trial, baseline estrogen levels were established as an independent prognostic predictor of time to castration-resistant prostate cancer. ...
Purpose:
Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer (PCa) owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized PCa.
Material and methods:
We studied 1793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors (5-ARIs) in the prospective PROCURE cohort for which preoperative plasma samples were obtained prior to radical prostatectomy (RP). Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Circulating levels were evaluated in relation to prognostic factors, disease-free survival (DFS), and metastasis-free survival (MFS), using multivariable Cox proportional hazards models.
Results:
At a median follow-up time of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease and 168 diseased. Higher levels of 11-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT) were observed in men with prostatic specific antigen (PSA) >20 ng/ml and positive nodal status (P<.05). In multivariable analyses, no significant association between 11-oxygenated androgens and DFS was observed. Adrenal 11β-hydroxyandrostenedione (11OHA4), the predominant androgenic 11KT, and its metabolite 11-ketoandrosterone (11KAST), modeled as quartiles, were associated with MFS (P=.06, .03, and 0.008, respectively). A significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in 5-ARIs patients (P<.001).
Conclusions:
Preoperative circulating 11-oxygenated androgen levels are associated with MFS in men with localized PCa undergoing RP and are affected by 5-ARI treatment.
... One of the biomarkers investigated is serum testosterone. In two previous studies using appropriate testosterone assay techniques, it was found that low tesosterone levels were associated with shorter time to death [9,10]. Although other studies also found an assocation between testosterone levels and survival in enzalutamide treated patients [11,12], adequate interpretation of results is hampered by their study design and techincal limitations of the applied immunoassays [13,14]. ...
... In total, 72 patients were included for further analysis and were stratified according to their testosterone levels (Low, ≤ 0.217 nmol/L; high, > 0.217 nmol/L; 6.3 ng/dL), based on the first quartile (Low) and the second to fourth quartile (High). This is a modified version of a previously described approach [9,10] Table 1. Median follow-up was 513 days for both PFS and FFS. ...
... Interestingly, more recent studies have found indications that baseline serum testosterone was associated with second-line hormone therapy outcomes in mCRPC patients. For example, Ryan et al. showed with data from the COU-AA-301 trial that patients treated with abiraterone acetate, a CYP17A1 inhibitor suppressing adrenal androgens, with higher baseline testosterone levels demonstrated longer median OS (18.9 vs. 10.4 months for > 0.298 nmol/L and ≤ 0.080 nmol/L, respectively) [9]. Other studies attempted similar analyses for patients treated with enzalutamide, abiraterone, and docetaxel, but lacked sensitive and accurate testosterone assays and were underpowered [11,12,20]. ...
Background
Enzalutamide is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, variances in responses are observed and there is a need for biomarkers predicting treatment outcome and selection. In this study, we aimed to explore the predictive value of testosterone for first-line enzalutamide treatment of mCRPC.
Methods
A retrospective analysis of 72 mCRPC patients with no prior abiraterone or docetaxel treatment was performed. Serum testosterone was measured using a liquid chromatography tandem-mass spectrometry method. Association of pre- and during-enzalutimide treatment testosterone levels with progression-free survival (PFS) and failure-free survival (FFS) was investigated using univariate and multivariate Cox models. Testosterone levels were dichotomized into a low (Q1) and high (interquartile range-Q4) group.
Results
Median PFS (7.4 v. 20.8 months, P<0.0001) and FFS (6.6 v. 17.7 months, P<0.0001) were shorter for patients with low testosterone levels (<0.217 nmol/L) during enzalutamide treatment. Furthermore, univariate Cox proportional hazards models revealed that low testosterone levels were associated with shorter PFS (HR 3.5, 95%CI 1.9-6.3; P<0.001) and FFS (HR 3.1, 95%CI 1.7–5.5; P<0.001). Pre-treatment testosterone levels were lower than during-treatment levels (P<0.0001) and low pre-treatment testosterone levels (<0.143 nmol/L) were associated with shorter median PFS (12.6 v. 20.5 months, P<0.01) and FFS (12.6 v. 22.5 months, P<0.01).
Conclusion
The results of this study suggest that low serum testosterone levels during and prior to enzalutamide treatment can predict progression in mCRPC patients and identifies tumors resistant to next-in-line enzalutamide treatment. Validation in a prospective cohort is warranted.
... When metabolized by prostate cells, DHEA can contribute up to one-sixth of dihydrotestosterone present in the prostate (44). In prostate cancer rat models, DHEA has been shown to confer protection against prostate cancer (45), while in patients, low serum levels of DHEA have been shown to correlate with high Gleason score, advanced clinical stage, and poor prognosis (46) in hormone-naïve prostate cancer (47), and worse cancer-specific survival among patients with mCRPC (48). These studies, however, have not correlated DHEA levels with G6PD expression or PPP activity. ...
The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.
... Abiraterone is a selective and irreversible inhibitor of CYP17, a key enzyme in the biosynthesis of androgens. 4 Large interpatient pharmacokinetic variability was shown for patients taking AA 1000 mg once daily, predominantly due to variation in absorption which is majorly affected by food intake. 5 Hence patients are instructed to take AA on an empty stomach. ...
Aims
To assess whether the exposure–response relation for abiraterone is different in pre‐chemotherapy patients compared to post‐chemotherapy patients with metastatic castration‐resistant prostate cancer (mCRPC).
Methods
Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression‐free survival [PFS] and overall survival [OS]). An interaction term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan–Meier analysis was used.
Results
In total, 98 mCRPC patients were included, of which 78 were pre‐chemotherapy and 20 were post‐chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect modifier. In pre‐chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42–1.10], P = .12 and HR 0.85 [95% CI 0.46–1.60], P = .61, PFS and OS, respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post‐chemotherapy patients (HR 0.30 [95% CI 0.12–0.74], P = .01 and HR 0.38 [95% CI 0.18–0.82] P = .01, PFS and OS, respectively), with an increased survival when exposed above this threshold.
Conclusion
Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure–response relation. No relation between abiraterone exposure and survival was seen for pre‐chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity.
... However, the efficacy of AA and prednisone in reducing intratumoral androgens in CRPC metastases has not been reported. Moreover, lower serum androgen levels prior to starting this regimen have been associated with worse outcomes in CRPC patients (12,13). Whether a similar association exists with intratumoral androgens levels prior to starting therapy, or with on-treatment androgen levels in serum or tissue is unknown. ...
... Nor is it accounted for by an increase in serum or intra-tumoral androgens above the levels originally achieved in response to AA plus prednisone. The observations that tumor steroid levels do not become re- The correlation of low baseline with low on-treatment adrenal androgen levels is of particular interest as lower adrenal androgens prior to therapy have been consistently associated with worse response to AA plus prednisone (13,(23)(24)(25). We show for the first time that this association with worse outcomes extends to low on-treatment level of DHEAS in serum and tissue, and with low adrenal androgens in pre-treatment metastasis biopsies. ...
... As such, patients with higher androgens may have better survival independent of an effect of AA. This is consistent with the association of lower serum androgen levels with decreased survival in both the placebo and AA arms of the phase III study of AA plus prednisone in men with metastatic CRPC (13), and with a recent meta-analysis demonstrating that PFS and OS were lower in CRPC patients with lower vs higher T levels (27). ...
Purpose:
In metastatic castration resistant prostate cancer (mCRPC) low serum androgens prior to starting Abiraterone Acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in CRPC metastases and associations of intratumoral androgens with response.
Experimental design:
We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2000mg at progression.
Results:
29 of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (p<0.001). Serum and tissue DHEAS remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pre-treatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on therapy) associated with rapid progression (20 vs 48 weeks p=0.0018; 20 vs 52 weeks p=0.0003; 14 vs 40 weeks p=0.0001; 20 vs 56 weeks p=0.02, respectively). One of 16 men escalating to 2000mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild type PTEN status associated with longer response (61 vs 33 weeks; p=0.02).
Conclusion:
Low circulating adrenal androgens levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. CRPC patients with higher serum DHEAS levels may benefit from dual-AR pathway inhibition, while those in the lowest quartile may require combinations with non-AR directed therapy.
... 10,11 Several attempts have been made to identify serum testosterone level as a biomarker for deciding treatment selection. 12,13 Recent studies observed that serum testosterone level affected therapeutic efficacy of abiraterone and enzalutamide. [14][15][16] However, the significance of pretreatment serum testosterone level on progression and survival in patients treated with enzalutamide for mCRPC remains limited. ...
... An subanalysis of the COU-AA 301 trial has shown that patients with lower testosterone level in postchemotherapy treatment with abiraterone have worse OS. 12 In this study, androstenedione and dehydroepiandrosterone sulfate also has similar relationship was observed, in addition to testosterone. Authors explained it by the hypothesis that serum testosterone might reflect the activity of the AR, and tumor with amplified AR might be hypersensitive to androgens. ...
... The proportion of adrenal testosterone in mice was calculated to be less than 5% in the results of this experiment. In clinical practice, the serum testosterone levels in healthy humans, at an average of 383 ng/dl (19), decreased to an average of 7.6 ng/dl after castration in the COU-AA-301 study of patients with CRPC (20). Moreover, serum testosterone levels averaged 7 ng/dl after castration and before abiraterone, decreasing to less than 1 ng/dl after abiraterone in the phase I study of abiraterone therapy (21). ...
Background/aim:
The in vivo effect of abiraterone on bone mineral density (BMD) in addition to androgen deprivation therapy was examined using a murine model.
Materials and methods:
The mice were separated into the following groups: control, abiraterone, castration, and castration+abiraterone. The percentage change in the ratio of bone to tissue volume (BV/TV), number of osteoblasts and osteoclasts, and the serum level of bone markers were compared on day 21.
Results:
The BV/TV ratio of the abiraterone, castration, and castration+abiraterone groups was lower than that of the control group. However, the change in the BV/TV ratio in the castration+abiraterone group was not significantly different from that in the castration group. There was no significant difference in the serum TRAP5b level and the number of osteoclasts and osteoblasts between the castration+abiraterone and the castration groups.
Conclusion:
The addition of abiraterone to castration did not affect BMD in the murine model.
